Within the pancreas are little spherical structures called islets of Langerhans – a name that might conjure up images of cells lazing on a remote beach, sipping tropical drinks. That picture could not be further from the truth: The so-called beta cells, the major component of these islets, are some of the busiest, most connected cells in our bodies. They do sip, but it is the sugar in our bloodstream they taste; they then secrete insulin back into the bloodstream to regulate the metabolism of that sugar. And, according to new Weizmann Institute research, these cells submit to a very tight organization. The study, which appeared in Cell Reports, revealed, for the first time, an image of beta cells that are “edgy.” The details of how beta cells are shaped may change our understanding of how they function and lead to new insights into how glucose is regulated in the body.

 

 

Beta cells are those affected by diabetes: In type 1 diabetes they are attacked by an autoimmune response in the body, and in type 2 diabetes the body cells do not respond to the insulin they secrete, which eventually leads to their dysfunction. The beta cells are a minority in the pancreas, but the island-like arrangement within the “sea” of pancreatic cells enables them to function as an organ within an organ. A closer look at the arrangement of cells in an islet of Langerhans shows that they assemble in “rosette” patterns around veins running through the pancreas, with small arteries encircling the rosettes.

 

Prof. Ben-Zion Shilo, research student Erez Geron and Dr. Eyal Schejter of the Molecular Genetics Department wanted to zoom in a bit closer – to the molecular arrangements of these cells. Many had assumed that the cells were polar – that they concentrate some functions on one side and others on the opposite side. Polarity, according to this view, would enable the beta cell to compartmentalize its activities, possibly sensing on one side and secreting on the other. In addition, beta cells are related to other polar cells – for example, those that line the intestine. But no one had actually managed to observe clear hallmarks of polarity in beta cells.  

To investigate, Geron studied proteins on the cells’ outer membranes – where sensing and secretion take place. Isolating individual islets of Langerhans from a mouse pancreas, he inserted a fluorescent protein into several of their cells. The team then devised a technique that allowed them to visualize filamentous actin, a major component of the cellular cytoskeleton, just within a few individual cells of each islet, thus providing good contrast right at the cells’ contours. Since islets of Langerhans can be kept alive in the lab dish, the researchers were able to observe the shapes of beta cells at work.
 

 

                                                           Cell design on a line

 

What they saw surprised them: Rather than a polar arrangement, the actin in the membrane formed stiff, linear edges, like those on a cube, along the length of the cell, giving it the appearance of an angular tent with poles. But these lines were more than just support poles: Numerous thin protrusions extended from the cell along these lines, and membrane features congregated along them – signaling proteins, channels for letting in glucose, others for trading short messages encoded in calcium ions with neighboring cells, and even outlets for secreting insulin.

Why do these particular cells reject their polar heritage and go for edgy shapes? Why would they take all of their functions – sensing glucose, releasing insulin and intercellular communication – and align them together along these cell edges? Shilo says that they do not yet have all the answers, but he and his group have some definite clues. For example, they think that keeping the sensing and secreting machinery close together could increase efficiency and/or cut down on response time.

Further research will be needed to understand the exact function of the edges, but Shilo says the study points to an important role in cell-to-cell communication. Indeed, one of the major implications of these findings is that, when it comes to cell design, relations between neighboring beta cells are critical. It is communication between cells that creates the tent-like shape in the first place: Beta cells that are cut off from the others soon lose their edges. And if the “tent poles” help facilitate communication, then the protrusions along their length are likely to play a role in passing messages back and forth, possibly by helping align the membranes’ pores, which are just big enough to admit the calcium ions. “These findings suggest a mechanism for beta cells to function in unison,” says Shilo. “Coordinating their actions might help prevent random responses by single cells.”

Although the work was done on mouse pancreatic cells, there is already some evidence that human beta cells also have edges. These findings, says Shilo, shed light on the ways that insulin-producing beta cells function, and they could lead to new ways of thinking about the normal complex, coordinated activity of these cells, which play such a central role in our health.
 
Prof. Ben- Zion Shilo's research is supported by the M.D. Moross Institute for Cancer Research; the Carolito Stiftung; and the Mary Ralph Designated Philanthropic Fund. Prof. Shilo is the incumbent of the Hilda and Cecil Lewis Professorial Chair of Molecular Genetics.

 

 

When in the 1880s Russian zoologist Ilya Mechnikov first described large, voracious cells that devour bacteria and cellular debris – findings for which he later received a Nobel Prize – he called them macrophages, or “big eaters.”  Although macrophages have since been assigned numerous additional responsibilities, both in immunity and in tissue maintenance, it is the “big-eater” label that has stuck for nearly 130 years.  But recent research at the Weizmann Institute, which recently appeared in Cell, is putting a new face on the macrophage. In fact, not only one face but many: These studies show that macrophages take on different functions and appearances depending on which tissue they call home.  Prof. Steffen Jung of the Immunology Department says: “If we can learn the tricks they use to change their functions, we might be able to harness their activities to control disease.”

 

The tasks that the macrophages carry out in the various organs can be highly specific. In the nervous system, for example, they play a role in shaping nerve cells, while in the spleen they dine on well-aged red blood cells. Jung, who has been studying macrophages for a decade, recently revealed that, unlike most immune cells, many macrophages are long-lived cells that arise in the embryo, developing alongside their host organs. These findings raised new questions about macrophage development. For example, how do they get trained to serve each particular organ and tissue?

To begin to answer these questions, Jung joined up with departmental colleague Dr. Ido Amit, who investigates how regulatory regions in the genome control immunity. There are only a handful of macrophages in any one organ, but Amit and his team have developed cutting-edge techniques, including advanced robotics and next-generation sequencing technologies, to study such rare, specialized cells in their natural state. The scientists profiled these cells down to the molecular level, using the data to explain the unique ways their genes are expressed and regulated.
 

 

 

        

 

The team, which also included Dr. Deborah Winter, Dr. Ronnie Blecher-Gonen, Eyal David and Dr. Hadas Keren-Shaul, all of the Weizmann Institute’s Immunology Department, and Yonit Lavin and Prof. Miriam Merad of the Icahn School of Medicine at Mount Sinai, New York, examined macrophages in seven different organs – from brain to lungs to intestines. They succeeded in identifying a unique signature for each of these populations, based on their genomic profiles and regulatory landscapes – a sort of textured map of their convoluted genetic activities. In particular, the team noted that each macrophage population used a distinct set of regulatory elements, or “enhancers,” for turning “on” or “off” the expression of certain genes.

Next the researchers switched these cells between organs. To their surprise, the macrophages began to change their signatures, taking on new profiles to fit their new surroundings. When the cells grew from immature cells, the revamping process was nearly complete – over 90%. But even when the experiment was repeated with fully differentiated cells, there were substantial changes in the macrophages’ personality profiles. Specifically, macrophages that were moved from the peritoneum to the lungs started to look and act like functional lung macrophages.

 

 

 

These findings, Amit and Jung believe, could change quite a few preconceived notions about macrophages. For one, these cells turn out to be incredibly plastic: “It’s a sort of ‘nature versus nurture’ issue,” says Winter, who led the study together with Blecher-Gonen. “Our findings suggest that nurture plays a much stronger role in shaping these cells’ identities than anyone had thought.” And the ways that the cells take their cues from their surroundings support Jung’s earlier findings: Macrophages arise from common precursor cells in the embryo and specialize after receiving signals from their host tissue, thus becoming an integral part of their surroundings. This goes beyond mere genetics, say the researchers: Understanding how the fate of such cells as macrophages is determined could help decipher the molecular mechanisms of diseases, including immunological disorders, anemia, leukemia and more.

 

The study was conducted in mice, but the ultimate goal is to apply the findings to humans. “In the future,” says Blecher-Gonen, “we want to learn how to retrain the macrophages ourselves. Then we could use them to treat diseases in which the patient’s macrophages are faulty or inadequate.” As an example, the team envisions creating lung macrophages that could clean up the thick secretions blocking the lungs of cystic fibrosis patients, or designer gut macrophages that could be used to treat irritable bowel disease. Amit: “Since most disease-causing mutations are located in regulatory regions, further studies could shed new light on the pathways involved in such diseases as inflammatory bowel disease and multiple sclerosis, and perhaps lead to the more precise treatment of patients.”

 

 

 

 

Ido Amit's research is supported by the M.D. Moross Institute for Cancer Research; the J&R Center for Scientific Research; the Jeanne and Joseph Nissim Foundation for Life Sciences Research; the Abramson Family Center for Young Scientists; the Wolfson Family Charitable Trust; the Abisch Frenkel Foundation for the Promotion of Life Sciences; the Leona M. and Harry B. Helmsley Charitable Trust; Sam Revusky, Canada; the Florence Blau, Morris Blau and Rose Peterson Fund; the estate of Ernst and Anni Deutsch; the estate of Irwin Mandel; and the estate of David Levinson. Dr. Amit is the incumbent of the Alan and Laraine Fischer Career Development Chair.
 

Prof. Steffen Jung's research is supported by the Leir Charitable Foundations; the Leona M. and Harry B. Helmsley Charitable Trust; the Maurice and Vivienne Wohl Biology Endowment; the Adelis Foundation; Lord David Alliance, CBE; the Wolfson Family Charitable Trust; the estate of Olga Klein Astrachan; and the European Research Council.